Project Summary Vascular risk factors (e.g. arterial stiffness and hypertension) are associated with cerebral small vessel disease, Alzheimer?s disease (AD) pathology and dementia. Further, myelin breakdown and/or fiber loss may be early events in the AD pathological process. Reduced white matter integrity commonly precedes AD pathologies, even in familial AD. Diffuse white matter disease is a late expression of ongoing microstructural abnormalities; yet, how abnormal cerebral perfusion in white matter contributes to the pathogenesis of AD has not been fully explored. Converging data suggest a relationship between APOE ?4 genotype and microvasculature dysfunction. APOE ?4 may contribute to altered cerebrovascular autoregulation (e.g., changes in blood flow), which hinders the white matter repair process. Moreover, impaired cerebral blood flow regulation is associated with longitudinal decline in vasoreactivity among people with insulin resistance, a condition which may promote AD pathology. Signs of cerebral vascular pathology, such as hypo-perfusion and impaired vascular reactivity, often coexist with more established markers associated with AD. To elucidate the relationships between cerebrovascular function and markers of white matter pathology, we propose to leverage the rich longitudinal cohort data from the Wake Forest Alzheimer?s Disease Core Center?s Clinical Core (P50 AG049638, PI. Craft), whose focus is on the contribution of metabolic and vascular factors to AD expression, with the addition of vascular reactivity imaging to the existing MRI. This application proposes to: 1) examine changes in white matter vascular functions and structures in adults at risk for AD using non-invasive novel MRI techniques; 2) evaluate the relationships between cerebral vascular reactivity, white matter structures, and known AD biomarkers (i.e. APOE, brain amyloid level, insulin resistance, and hypertension); and 3) advance our knowledge of possible cerebrovascular biomarkers causing diffuse white matter disease among people with risk factors of cognitive decline.